The implementation of molecularly targeted imaging modalities has progressed considerably in recent years. Fluorophores in the near-IR range are of particular interest for in vivo optical imaging due to the significant tissue penetration of light in this range. One such agent, indocyanine green, is FDA approved and currently involved in over 100 active clinical trials, including over 30 for cancer diagnosis. Moreover, fluorescence-guided surgery methods that use targeted agents to demarcate tumor margins are progressing rapidly in a clinical context. Despite a central role in modern biology and medicine, the compounds employed in near-IR fluorescence techniques have changed little in recent decades. In fact, many of these agents were developed for laboratory methods (i.e. DNA sequencing) and not clinical use. Using molecular design concepts borrowed from related fields (e.g. medicinal chemistry and complex molecule synthesis), we seek to develop new agents with improved utility for cancer-related imaging. The long-term goal is to identify develop readily synthesized, stable, and bright fluorophores with optimal properties for biomedical imaging. To date, our efforts have centered on the heptamethine cyanine class of near-IR fluorophores, which, among many other applications, are being investigated extensively for use in fluorescence-guided surgery. We have developed a new rearrangement reaction that enables the synthesis of previously inaccessible of cyanine fluorophores. Compared to existing agents, these compounds exhibited improved optical properties and, most importantly, significantly greater chemical stability to biological nucleophiles. We have shown that these new agents, when conjugated to the anti-HER1 antibody, panitumumab, exhibit useful fluorescence properties in microscopy experiments and excellent in vivo imaging properties. An additional area of interest is the synthesis and study of natural products with useful optical properties. Many natural products have evolved to, at least in part, interact with light, and derivatives of some including umbelliferone, are key fluorophores in modern biology. We completed the total synthesis of the eudistidine alkaloids, and are currently examining the biological and optical properties of these molecules. My lab is in also interested in a natural product with close structural homology to the cyanine class of fluorophores. We anticipate this compound may exhibit useful optical switching properties with utility for various microscopy applications. At this stage, we are developing a concise synthesis that will enable efficient access to this promising compound.